U.S. patent number 3,853,872 [Application Number 05/363,455] was granted by the patent office on 1974-12-10 for 2,3,4,5-substituted thiazoles.
This patent grant is currently assigned to American Home Products Corporation. Invention is credited to Stanley C. Bell, Peter H. L. Wei.
United States Patent |
3,853,872 |
Wei , et al. |
December 10, 1974 |
2,3,4,5-SUBSTITUTED THIAZOLES
Abstract
Pharmacologically active compounds have been prepared of the
following general formulae: The compounds are active as CNS
depressants, antitubercular agents and mood elevators.
Inventors: |
Wei; Peter H. L. (Springfield,
PA), Bell; Stanley C. (Penn Valley, PA) |
Assignee: |
American Home Products
Corporation (New York, NY)
|
Family
ID: |
26823554 |
Appl.
No.: |
05/363,455 |
Filed: |
May 24, 1973 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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125412 |
Mar 17, 1971 |
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Current U.S.
Class: |
540/568; 514/924;
544/278; 548/154 |
Current CPC
Class: |
C07D
513/04 (20130101); Y10S 514/924 (20130101) |
Current International
Class: |
C07D
513/04 (20060101); C07D 513/00 (20060101); C07d
051/46 () |
Field of
Search: |
;260/251A,36.7T,256.5R |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rush; Raymond V.
Attorney, Agent or Firm: Bellino; Vito Victor
Parent Case Text
RELATED APPLICATIONS
This application is a continuation-in-part of co-pending
application of Ser. No. 125,412, filed Mar. 17, 1971, and now
abandoned.
Claims
What is claimed is:
1. A compound selected from the group consisting of those of the
formulae: ##SPC3##
wherein R.sub.1 is selected from the group consisting of hydrogen,
(lower)alkyl, halogen and trifluoromethyl;
R.sub.2 is selected from the group consisting of hydrogen and
(lower)alkyl;
n is an integer of from two to four, inclusive;
m is the integer one or two; and the pharmaceutically acceptable
acid salts thereof.
2. A compound, as set forth in claim 1 which is:
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ac
etic acid, hydrobromide.
3. A compound, set forth in claim 1 which is:
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ac
etic acid, ethyl ester, hydrobromide.
4. A compound, as set forth in claim 1, which is:
3-(p-chlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-acetic acid,
ethyl ester, hydrobromide.
5. A compound, as set forth in claim 1, which is:
2,3,5,6-tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, ethyl ester, hydrobromide.
6. A compound, as set forth in claim 1, which is:
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ac
etic acid, methyl ester, hydrobromide.
7. A compound, as set forth in claim 1, which is
3-(p-chlorophenyl)-2,3,6,7-tetrahydro-3-hydroxy-5H-thiazolo[3,2-a]pyrimidi
ne-2-acetic acid, ethyl ester, hydrobromide.
8. A compound, as set forth in claim 1, which is:
2,3,5,6-tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, methyl ester, hydrobromide.
9. A compound, as set forth in claim 1, which is:
3-(p-chlorophenyl)-2,3,6,7-tetrahydro-3-hydroxy-5H-thiazolo[3,2-a]pyrimidi
ne-2-acetic acid, hydrobromide.
10. A compound, as set forth in claim 1 which is:
3-(p-chlorophenyl)-2,3,5,6,7,8-hexahydro-3-hydroxythiazolo[3,2-a][1,3]diaz
epine-2-acetic acid, hydrobromide.
Description
BACKGROUND OF THE INVENTION
Substituted thiazoles have been prepared in the past by the two
step reaction of (1) an alpha-halo ketone with an alkylene thiourea
to afford a 3-hydroxy[2, 1-b]thiazole derivative, followed by (2)
dehydration of the 3-hydroxy group in the presence of an acid. The
first reaction step is conventionally conducted in a solvent such
as acetone or a lower alkanol at a temperature from about
20.degree. to 50.degree.C. for a period of from about 3 to 48
hours. The second reaction step is conducted at from room
temperature to about 100.degree.C. in the presence of an acid such
as hydrochloric acid, hydrobromic acid or acetic acid, optionally
in the presence of a solvent such as a lower alkanol, acetone or
tetrahydrofuran. Exemplary of this process is that of Houlihan et.
al., U.S. Pat. No. 3,507,869.
DESCRIPTION OF THE INVENTION
This invention is concerned with the preparation of novel
pharmacologically active compounds of the general formulae:
##SPC1##
Wherein R.sub.1 is selected from the group consisting of hydrogen,
(lower)alkyl, halogen, phenyl, trifluoromethyl, nitro, amino, and
(lower)alkoxy; R.sub.2 is selected from the group consisting of
hydrogen and (lower)alkyl; n is an integer of from two to four; m
is one of the integers one and two; and the pharmaceutically
acceptable acid addition salts thereof.
The compounds of the invention are prepared by the following
process: ##SPC2##
Wherein R.sub.1, R.sub.2, n, and m are the same as hereinabove
described; and X is a halogen.
The 3-hydroxyimidazothiazole intermediates may be isolated by
interrupting the process before it has progressed completely to the
dehydrated product. It is to be understood that during the reaction
a preponderance of the 3-hydroxyimidazothiazole is initially
present, with continuing increase in the ratio of the dehydrated
product as the reaction proceeds. The ratio of
3-hydroxyimidazothiazole to the dehydrated product at any given
time during the reaction varies with the specific reactants and the
other reaction parameters. However, optimization in the yield of
either the intermediate or the unsaturated final product is readily
achieved for any given system by removing an aliquot sample of the
reaction mixture and determining the ratio of its components by
standard means such as thin layer chromatography or infra red
analysis.
Although the reaction proceeds in the presence of inorganic as well
as organic acids such as hydrochloric, hydrobromic phosphoric,
acetic and propionic acid, optionally in the presence of an inert
solvent such as ethanol, isopropanol, acetone, tetrahydrofuran, and
the like, it is preferred to employ acetic acid and more preferably
glacial acetic acid because the latter acids serve as satisfactory
solvents for the reaction mixture.
Thus, the preferred method of preparation comprises admixing the
reactants in glacial acetic acid and heating them on a steam bath
until the reaction is complete. The reaction mixture is filtered
and the solvent is evaporated. The residue may then be further
purified by recrystallization from an appropriate organic solvent
such as acetonitrile. The reaction time needed for production of
the 3-hydroxy derivatives extends from the dissolution time in the
solvent employed up to about 3.5 hours at steam bath temperature.
The unsaturated products result from extended heating, such as
overnight on a steam bath.
In the evaluation of the biological activity of the compounds of
the invention, the in vivo effects were tested as follows: Each
compound tested was administered orally or intraperitoneally to
three mice (14 to 24 grams) at each of the following doses: 400,
127, 40 and 12.7 milligrams per kilogram of host body weight (MPK).
The animals were watched for a minimum of 2 hours during which time
signs of general stimulation, (i.e., increased spontaneous motor
activity, hyperactivity on tactile stimulation, twitching), general
depression (i.e., decrease spontaneous motor activity, decreased
respiration) and autonomic activity (i.e., miosis, mydriases,
diarrhea) were noted. The date obtained, demonstrated that the
compounds of the invention induce central nervous system depressant
effects at a dose of 127 to 400 MPK. Thus the compounds of the
invention have utility as pharmacologically active compounds in
experimental and comparative pharmacology and are of value in the
treatment of mammals, e.g., mice, rats, etc., who are responsive to
treatment with central nervous system depressant agents.
Specifically the compounds may be administered for the purpose of
inducing a sedative or calming effect in mammals.
In addition, the compounds evidence usefulness as effective mood
elevators in that they block reserpine induced ptosis at a dosage
level as low as 0.12 milligrams per kilogram body weight, a
characteristic property of known mood elevators such as Amphetamine
and Tofranil. This property of the compounds was determined by oral
administration of each compound in a number of graded doses to
groups of six mice (3 male and 3 female) followed in 1 hour by
challenge with 2.5 milligrams of reserpine per kilogram body
weight. The degree of ptosis for each eye was determined at 1 hour
and 2 hour intervals post treatment and compared with
simultaneously run control animals. The ED50 in milligrams per
kilogram body weight as antagonists to reserpine ptosis for each of
the specifically tested compounds is provided at the end of the
title for each working example, infra. In general, a dose at or
below 10 milligrams per kilogram body weight is considered to
evidence very potent anti-reserpine activity.
When the compounds of the invention are employed as described
above, they may be administered alone or in combination with
pharmacologically aceptable carriers, the proportion of which is
determined by the solubility and chemical nature of the compound,
chosen route of administration and standard pharamacological
practice. For example, they may be administered orally in the form
of tablets or capsules containing such excipients as starch, milk
sugar, calcium carbonate and the like. They may be administered
orally in the form of solutions which amy contain coloring or
glucose in a sufficient quantity to render the solution
isotonic.
The dosage of these agents will vary with the route of
administration and the particular compound chosen.
The following compounds have also demonstrated in vitro
antitubercular activity at concentrations as low as the stated
value:
2,3,5,6-tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, ethyl ester, hydrobromide at 5 ug/ml;
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]-thiazole-2-ac
etic acid, ethyl ester, hydrobromide at 5 ug/ml;
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ace
tic acid, methyl ester, hydrobromide at 1 ug/ml; and
2,3,5,6-tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, methyl ester, hydrobromide at 5 ug/ml.
These compounds are useful for the in vitro inhibition of M.
tuberculosis. The compounds thus may be employed for example in
hospitals, sanitariums and the like to effectively inhibit the
causative organism of tuberculosis by contacting infected areas and
materials with aqueous solutions or dispersions of said compounds.
The compounds noted completely inhibit Mycobacterium tuberculosis,
human type, strain H37Rv when applied as an aqueous solution of
dispersion.
The terms halo and halogen are meant to identify chlorine, bromine
and iodine. The term (lower)alkyl is used to include straight and
branched chain hydrocarbon groups containing from 1 to 6 carbon
atoms such as methyl, ethyl, i-propyl n-butyl, n-hexyl, and the
like. The term (lower) alkoxy is used to include those
hydrocarbonoxy groups such as methoxy, ethoxy, n-propoxy, n-butoxy,
and the like. The term pharmaceutically acceptable acid is used to
include non-toxic salts such as those which are formed by reaction
with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and
similar acids known to the art.
The following specific examples illustrate the preparation of the
3-hydroxy compounds of this invention under neutral conditions
(Examples 1A) as well as the production of 3-hydroxy compounds and
the dehydrated products thereof under acidic reaction conditions
(Examples 1B-9). The advantage of acidic reaction conditions being
employed in the production of either the 3-hydroxy compounds or the
dehydrated product thereof is self-evident. Each of the 3-hydroxy
substituted compounds specifically exemplified undergo dehydration
upon heating for a period up to about 16 hours as is illustrated in
Example 3.
EXAMPLE 1
3-(p-Chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ace
tic acid, hydrobromide. ED 50-0.22.
A. A dimethoxyethane solution of 2-imidazolidinethione (2.04 g,
0.02 m) and 3-bromo-3-(p-chlorobenzoyl)propionic acid (5.82 g, 0.02
m) containing 10 ml of dimethylformamide was heated on a steam bath
for 2 hours. The white solid was collected and dried, and weighed
7.5 g. The crude material was recrystallized from a mixture of
ethanol and dimethoxyethane. The pure hydrobromide of
3-(p-chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazoleaceti
c acid melted at 273-5.degree.C.
Elemental Analysis for: C.sub.13 H.sub.13 CIN.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 39.66; H, 3.58; Br, 20.30; Cl, 9.01; N, 7.12; S,
8.14.
Found: C, 39.56; H, 3.75; Br, 20.06; Cl, 8.90; N, 6.83; S, 8.23.
The IR spectrum indicated the presence of acid group at 5.8 .mu.
and OH at 3.15 .mu..
B. This compound (16 g) was also obtained by heating a glacial
acetic acid solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid
(11.64 g, 0.04 m) and 2-imidazolidinethione (4.49 g, 0.044 m) on a
steam bath for 31/2 hours.
C. Additional heating of the title compound affords
3-(p-chlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-acetic acid,
hydrobromide.
EXAMPLE 2
3-(p-Chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ace
tic acid, ethyl ester, hydrobromide ED50-0.27
A mixture of 3-bromo-3-(p-chlorobenzoyl)propionic acid, ethyl ester
(6.5 g, 0.02 m) and 2-imidazolidinethione (2.2 g, 0.022 m) was
dissolved in glacial acetic acid on a steam bath. After
dissolution, the solution was filtered and the solvent was
evaporated. The residue was treated with diethyl ether and the
solid (7.5 g) was collected. The crude material was recrystallized
from acetonitrile, m.p. 163-4.degree.C.
Elemental analysis for C.sub.15 H.sub.17 ClN.sub.2 O.sub.3 S.sup..
Br:
Calc'd: C, 42.72; H, 4.30; Br, 18.95; Cl, 8.41; N, 6.65; S,
7.60.
Found: C, 42.86; H, 4.03; Br, 18.56; Cl, 8.23; N, 6.62; S,
7.65.
The IR spectrum showed absorptions for OH and amine salt and 3.3
.mu., ester at 5.85 .mu., C=N at 6.25 .mu.. The NMR spectrum
(DMSO-d.sub.6) showed aromatic protons at 7.7 .sigma., ethylene,
methine, methylene and protons of the ethoxy group at 4.0 .sigma.,
methylene protons of the acetic group at 2.9 .sigma., methyl
protons of ethoxy group at 1.2 .sigma..
EXAMPLE 3
3-(p-Chlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-acetic acid,
ethyl ester, hydrobromide ED50-3.20.
A glacial acetic acid solution of
3-bromo-3-(p-chlorobenzoyl)propionic acid, ethyl ester (6.4 g, 0.02
m) and 2-imidazolidinethione (2.2 g, 0.022 m) was heated on a steam
bath overnight. After having been filtered from some insoluble
material, the solvent was removed. The residual solid was slurried
with dimethoxyethane and collected (7.5 g). The crude material was
recrystallized from acetonitrile and the analytical sample has a
melting point of 217-8.degree.C.
Elemental analysis for C.sub.15 H.sub.16 BrClN.sub.2 O.sub.2 S:
Calc'd: C, 44.62; H, 4.00; N, 6.94; S, 7.96.
Found: C, 44.51; H, 3.95; N, 7.24; S, 7.78.
The IR spectrum showed absorption for ester at 5.75 .mu. and C=N
and C=C at 6.25 .mu.. The NMR spectrum showed aromatic protons at
7.8 .sigma. (s); ethylene protons at 4.4 .sigma. (s);
acetylmethylene protons at 3.8 .sigma. (s) and ethoxy at 4.2
.sigma. (q) and 1.2 .sigma. (t) also exchangeable proton at 10.0
.sigma..
EXAMPLE 4
2,3,5,6-Tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, ethyl ester,, hydrobromide ED50-3.90
A. By following the procedure of Example 2, and by substituting
3-benzoyl-3-bromopropionic acid, ethyl ester for
3-bromo-3-(p-chlorobenzoyl)propionic acid, ethyl ester we obtained
the titled compound. The crude material (9.0 g), which was prepared
from 0.04 mole of starting ester, was recrystallized from acetone,
to afford the analytically pure sample, m.p. 147-9.degree.C.
Elemental Analysis for C.sub.15 H.sub.18 N.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 46.51; H, 4.95; Br, 20.64; N, 7.24; S, 8.28.
Found: C, 46.38; H, 4.94; Br, 20.52; N, 7.08; S, 8.38.
Ir: oh and amine HBr, 3.3 .mu.; ester, 5.8 .mu.; amine HBr, 6.2
.mu.. NMR (DMSO-d.sub.6): aromatic, 7.5 .sigma. (m); ethoxy, 4.0
.sigma. (q) and 1.2 .sigma. (t); other aliphatic spread between 2.8
to 4.8 .sigma..
B. Following the prolonged heating technique of Example 3 affords
3-phenyl-5,6-dihydroimidazo[2,1-b]thiazolo-2-acetic acid, ethyl
ester, hydrobromide.
EXAMPLE 5
3-(p-Chlorophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-ace
tic acid, methyl ester, hydrobromide ED50-0.50
By following the procedure of Example 2 and by substituting the
ethyl ester with methyl ester, we prepared the titled compound.
From 0.0218 mole of starting ester 8.5 g of crude material was
obtained. After recrystallization from methanol the compound had a
melting point of 173-4.degree.C.
Elemental Analysis for c.sub.14 H.sub.15 ClN.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 41.24; H, 3.96; Br, 19.60; Cl, 8.70; N, 6.87; S,
7.86.
Found: C, 41.34; H, 3.99; Br, 19.79; Cl, 8.77; N, 6.88; S,
7.96.
Ir: oh and amine HBr, 3.4 .mu. (b); ester, 5.85 .mu. (s); amine
HBr, 6.3 .mu. (s). NMR (DMSO): aromatic, 7.6 .sigma. (s);
OCH.sub.3, 3.65 .sigma. (s); other aliphatic spread from 2.8
.sigma. to 4.8.sigma..
EXAMPLE 6
3-p-Chlorophenyl)-2,3,6,7-tetrahydro-3-hydroxy-5H-thiazolo-[3,2-a]pyrimidin
e-2-acetic acid, ethyl ester, hydrobromide ED50-0.12.
A. By following the procedure of Example 2, and by substituting
2-mercapto tetrahydropyrimidine (0.04 mole) for
2-mercaptoimidazoline we obtained the titled compound. The oily
residue that remained after removal of solvent was treated with
dimthoxyethane, and the crude solid weighed 16.2 g. The
recrystalllized sample (from acetonitrile) melted at
180-2.degree.C.
Elemental Analysis for C.sub.16 H.sub.19 ClN.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 44.20; H, 4.40; Br, 18.38; N, 6.45; S, 7.37.
Found: C, 43.89; H, 4.65; Br, 18.37; N, 6.56; S, 7.20.
Ir: oh, 3.2 .mu.; amine HBr, 3.4 .mu.; ester 5.75 .mu.; amine HBr
6.1 .mu..
Nmr (dmso): aromatic, 7.6 .sigma.; ethoxy, 4.0 .sigma. and 1.2
.sigma.; other aliphatic spread between 2.0 to 4.4 .sigma..
B. Following the prolonged heating technique of Example 3 affords
3-(p-chlorophenyl)-6.7-dihydro-5H-thiazolo
[3,2-a]pyrimidine-2-acetic acid, ethyl ester, hydrobromide.
EXAMPLE 7
2,3,5,6-Tetrahydro-3-hydroxy-3-phenylimidazo[2,1-b]thiazole-2-acetic
acid, methyl ester, hydrobromide. ED50-0.50
By following the procedure of Example 2 and by substituting
3-benzoyl-3-bromopropionic acid, methyl ester (0.06 mole) for
3-bromo-3-(p-chlorobenzoyl)propionic acid, ethyl ester we obtained
the titled compound. The oily residue that remained after removal
of solvent was dissolved in acetone. After having been filtered
from some insoluble material, the filtrate yielded 16.0 g. The
compound after recrystallization from acetonitrile melted at
169-70.degree.C.
Elemental Analysis for C.sub.14 H.sub.16 N.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 45.05; H, 4.59; Br, 21.41; N, 7.51; S, 8.59.
Found: C, 44.97; H, 4.55; Br, 21.30; N, 7.67; S, 8.51.
Ir: oh and amine HBr, 3.3 .mu.; ester, 5.8 .mu.; amine HBr 6.3
.mu..
Nmr (dmso-d.sub.6): aromatic, 7.6 .sigma.; OCH.sub.3, 3.6 .sigma.
(s); other aliphatic spread from 2.8 .sigma. to 4.8 .sigma..
EXAMPLE 8
3-(p-Chlorophenyl)-2,3,6,7-tetrahydro-3-hydroxy-5H-thiazolo
[3,2-a]pyrimidine-2-acetic acid, hydrobromide. ED50-0.25
By following the procedure B of Example 1, and by substituting
2-mercapto tetrahydropyrimidine (0.088 mole) for
2-mercaptoimidazoline, we obtained 32 g of the crude tilted
compound. The sample recrystallized from acetonitrile melted at
176-7.degree.C.
Elemental Analysis for C.sub.14 H.sub.15 ClN.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 41.24; H, 3.96; Br, 19.60; Cl, 8.70; N, 6.87; S,
7.86.
Found: C, 41.24; H, 3.85; Br, 19.60; Cl, 8.69; N, 7.19; S,
8.10.
Ir: oh and amine HBr, 3.3 .mu.; carboxylic acid, 5.8 .mu.; amine
HBr, 6.15 .mu.. NMR (DMSO): aromatic, 7.6 .sigma.; aliphatic spread
between 2.1 .sigma. to 4.4 .sigma..
EXAMPLE 9
3-(p-Chlorophenyl)-2,3,5,6,7,8-hexahydro-3-hydroxythiazolo-[3,2-a][1,3]diaz
epine-2-acetic acid, hydrobromide. ED50-98.00
A. By following the procedure B of example 1 and by substituting
2-mercapto tetrahydrodiazepine (0.044 mole) for
2-mercaptoimidazoline, we obtained the titled compound. The oily
residue that was obtained after removal of the solvent was treated
with acetone to give 14.0 g of the crude titled compound. The crude
material recrystallized from acetonitrile gave pure product, m.p.
165-7.degree.C.
Elemental Analysis for C.sub.15 H.sub.17 ClN.sub.2 O.sub.3 S.sup..
HBr:
Calc'd: C, 42.72; H, 4.30; Br, 18.95; Cl, 8.41; N, 6.65; S,
7.59.
Found: C, 42.68; H, 4.43; Br, 19.03; Cl, 8.45; N, 6.84; S,
7.64.
Ir: oh, 3.2 .mu.; amine HBr, 3.4 .mu.; carboxylic acid, 5.75 .mu.;
amine HBr, 6.2 .mu.. NMR (DMSO): aromatic 7.7 .sigma.; methine, 4.4
.sigma.; 5.9 methylene, 3.7 .sigma.; acetyl methylene, 2.6 .sigma.;
6.7-ethylene, 2.0 .sigma..
B. Following the prolonged heating technique of Example 3 affords
3-(p-chlorophenyl)-5,6,7,8-tetrahydro-thiazolo-[3,2-a-][1,3]diazepine-2-ac
etic acid, hydrobromide.
EXAMPLE 10
3-(p-Ethylphenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazolo-2-acet
ic acid, hydrobromide.
Following the procedure of Example 1 (B), with the exception that
3-bromo-3(p-ethylbenzoyl)propionic acid is reacted with
2-imidazolidinethione,, affords the title compound.
EXAMPLE 11
3-(o-Isopropylphenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-
acetic acid, ethyl ester, hydrobromide.
Following the procedure of Example 2, with the exception that
3-bromo-3(o-isopropylbenzoyl)propionic acid, ethyl ester is reacted
with 2-imidazolidinethione, affords the title compound.
EXAMPLE 12
3-(Biphenylyl-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-acetic
acid, hydrobromide.
Following the procedure of Example 1 (B), with the exception that
3-bromo-3-(p-phenylbenzoyl)propionic acid is reacted with
2-imidazolidinethione, yields the title compound.
EXAMPLE 13
3-(p-Trifluoromethylphenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo
[2,1-b]thiazole-2-acetic acid, hydrobromide.
The title compound is obtained following the procedure of Example 1
(B) by reacting 3-bromo-3(p-trifluoromethylbenzoyl)-propionic acid
with 2-imidazolidinethione.
EXAMPLE 14
3-(p-Nitrophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-acet
ic acid, ethyl ester, hydrobromide.
The title compound is produced by reacting
3-bromo-3(p-nitrobenzoyl)propionic acid, ethyl ester with
2-imidazolidinethione following the procedure of Example 2.
EXAMPLE 15
3-(p-Aminophenyl)-2,3,5,6-tetrahydro-3-hydroxyimidazo[2,1-b]thiazole-2-acet
ic acid, hydrobromide.
The title compound is produced by hydrogenation of the product of
Example 14 or by reaction of 3-bromo-3(p-aminobenzoyl)propionic
acid with 2-imidazolidinethione following the procedure of Example
1 (B).
EXAMPLE 16
3-Anisyl-5,6-dihydroimidazo[2,1-b]thiazole-2-acetic acid, ethyl
ester, hydrobromide.
The title compound is prepared by reacting
3-bromo-3-anisoyl-propionic acid, ethyl ester with
2-imidazolidinethione in accordance with the procedure of Example
3.
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